Despite extensive progress in understanding the pathology of Alzheimer's disease (AD) over the last 50 years, clinical trials based on the amyloid-beta (Aβ) hypothesis have kept failing in late stage human trials. As a result, just four old drugs of limited clinical outcomes and numerous side effects are currently used for AD therapy. This article assesses the common pharmacological targets and therapeutic principles for current and future drugs. It also underlines the merits of natural products acting through a polytherapeutic approach over a monotherapy option of AD therapy. Multi-targeting approaches through general antioxidant and anti-inflammatory mechanisms coupled with specific receptor and/or enzyme-mediated effects in neuroprotection, neuroregeneration, and other rational perspectives of novel drug discovery are emphasized.
Keywords: Alzheimer’s disease; acetylcholinesterase; amyloid beta; anti-inflammatory; antioxidant; cholinergic; tau protein.